Genetic and Molecular Drivers of Scleroderma Pathogenesis.

Scleroderma is a heterogeneous disease with various clinical findings involving immune dysregulation, vasculopathy, and fibrosis. Biologic and genetic studies over recent decades have elucidated molecular mechanisms of scleroderma pathogenesis. Genetic association studies have identified interferon and other immune regulatory genes as strongly linked to scleroderma risk, highlighting the immune system as a fundamental determinant of disease.

Cross-tissue organization of myeloid cells in scleroderma and related fibrotic diseases.

Purpose Of Review: Scleroderma and other fibrotic diseases have been investigated using single-cell RNA sequencing (scRNA-Seq), which has demonstrated enrichment in myeloid cell populations in multiple tissues. However, scRNA-Seq studies are inconsistent in their nomenclature of myeloid cell types, including dendritic cells, monocytes, and macrophages. Using cell type-defining gene signatures, I propose a unified nomenclature through analysis of myeloid cell enrichment across fibrotic tissues.

Gene trajectory inference for single-cell data by optimal transport metrics.

Single-cell RNA sequencing has been widely used to investigate cell state transitions and gene dynamics of biological processes. Current strategies to infer the sequential dynamics of genes in a process typically rely on constructing cell pseudotime through cell trajectory inference. However, the presence of concurrent gene processes in the same group of cells and technical noise can obscure the true progression of the processes studied.

IL-6 trans-signaling in a humanized mouse model of scleroderma.

Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSCs).

Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.

Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs.

Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor.

Morphea after -induced facial nerve palsy.

Morphea, also known as localized scleroderma, is characterized by inflammation and fibrosis of the skin. The exact pathogenesis of morphea is unknown, but generally includes genetic predisposition to autoimmunity combined with an environmental insult. Previous cases have been associated with active infection; however, infection as a direct cause of morphea was not generalizable to most patients.

Publisher Correction: HER2 joins AKT to inhibit STING immunity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Microbiome: Ecology of eczema.

Patients with atopic dermatitis have fundamentally different skin microbial populations compared with people with healthy skin. Bacteria associated with atopic dermatitis express genes for survival in dry conditions and for ammonia production, modulating the pH of this distinct environment and driving complex ecological interactions.

Somatic p.T771R KDR (VEGFR2) Mutation Arising in a Sporadic Angioma During Ramucirumab Therapy.

Importance: Inhibition of angiogenesis is an effective anticancer strategy because neoplasms require a rich blood supply. Ramucirumab, approved by the US Food and Drug Administration in 2014 to treat gastric adenocarcinomas and non-small cell lung carcinomas, targets vascular endothelial growth factor 2 (VEGFR2). We identified a patient prescribed a regimen of irinotecan hydrochloride, cetuximab, and ramucirumab for metastatic rectal cancer (diagnosed in November 2013 and treated through early January 2015) who developed a new-onset, expanding vascular lesion on his right leg.

Optimizing direct immunofluorescence.

Immunofluorescence is a laboratory technique that utilizes a fluorophore-labeled antibody to detect immune complexes in tissue. Most of the labeled antibodies used in a clinical laboratory bind the conserved domains within each class of human antibodies, allowing them to detect a wide range of autoimmune complexes. Drawbacks to this technique mostly relate to proper handling of the specimen and the fluorophore-labeled antibodies.

Rules of engagement for base excision repair in chromatin.

Most of the DNA in eukaryotes is packaged in tandemly arrayed nucleosomes that, together with numerous DNA- and nucleosome-associated enzymes and regulatory factors, make up chromatin. Chromatin modifying and remodeling agents help regulate access to selected DNA segments in chromatin, thereby facilitating transcription and DNA replication and repair. Studies of nucleotide excision repair (NER), single strand break repair (SSBR), and the homology-directed repair (HDR), and non-homologous end-joining (NHEJ) double strand break repair pathways have led to an "access-repair-restore" paradigm, in which chromatin in the vicinity of damaged DNA is disrupted, thereby enabling efficient repair and the subsequent repackaging of DNA into nucleosomes.

Nucleosome disruption by DNA ligase III-XRCC1 promotes efficient base excision repair.

Each day, approximately 20,000 oxidative lesions form in the DNA of every nucleated human cell. The base excision repair (BER) enzymes that repair these lesions must function in a chromatin milieu. We have determined that the DNA glycosylase hNTH1, apurinic endonuclease (APE), and DNA polymerase β (Pol β), which catalyze the first three steps in BER, are able to process their substrates in both 601- and 5S ribosomal DNA (rDNA)-based nucleosomes.

Non-specific DNA binding interferes with the efficient excision of oxidative lesions from chromatin by the human DNA glycosylase, NEIL1.

Although DNA in eukaryotes is packaged in nucleosomes, it remains vulnerable to oxidative damage that can result from normal cellular metabolism, ionizing radiation, and various chemical agents. Oxidatively damaged DNA is repaired in a stepwise fashion via the base excision repair (BER) pathway, which begins with the excision of damaged bases by DNA glycosylases. We reported recently that the human DNA glycosylase hNTH1 (human Endonuclease III), a member of the HhH GpG superfamily of glycosylases, can excise thymine glycol lesions from nucleosomes without requiring or inducing nucleosome disruption; optimally oriented lesions are excised with an efficiency approaching that seen for naked DNA [1].

Rapid species identification within the Mycobacterium chelonae-abscessus group by high-resolution melting analysis of hsp65 PCR products.

Polymerase chain reaction (PCR) amplification of the heat shock protein 65 (hsp65) gene followed by high-resolution melting analysis with LCGreen I (Idaho Technology, Salt Lake City, UT) was used to differentiate the mycobacteria species Mycobacterium chelonae, Mycobacterium abscessus, and Mycobacterium immunogenum in less than 20 minutes. A 105-base-pair amplicon that clustered the different species by predicted melting temperature was found from available GenBank hsp65 sequences. We identified 24 clinical isolates within the M chelonae-abscessus group by proximal 16S ribosomal RNA and hsp65 gene sequencing.